Candidate: Jason Griffith, M.D./Ph.D., is an Assistant in Medicine in the Division of Pulmonary and Critical Care at Massachusetts General Hospital (MGH) and an Instructor of Medicine at Harvard Medical School (HMS). He received his M.D./Ph.D. from Yale University, where he studied the innate immune response to malaria in the laboratory of Dr. Richard Bucala. After Dr. Griffith?s clinical training, he joined the laboratory of Dr. Andrew Luster at the Center for Immunology and Inflammatory Diseases (CIID) at MGH, where he has focused on the role of Regulatory T cells (Tregs) in modulating the immune response to influenza. The short term-goals of this K08 award resubmission are to provide training in adaptive immunology, advanced microscopy, and genomic techniques. Dr. Griffith?s long-term goal is to develop an independent R01 funded research program studying the factors that modulate the host response to respiratory viral infection. Environment: Dr. Griffith will perform the work in this proposal in the CIID at MGH, under the mentorship of Drs. Andrew Luster and Benjamin Medoff. The CIID is a state-of-the-art multidisciplinary research center focused on mechanisms of immune-mediated inflammatory diseases and is the foundation for immunology research at MGH. Additionally, Dr. Griffith has organized a Training Advisory Committee consisting of Drs. Lawrence Turka, Nir Hacohen, and Thorsten Mempel to provide expertise and training in Treg biology, advanced genomic techniques, and advanced microscopic imaging. Dr. Griffith will additionally attend meetings and complete didactic courses in adaptive immunology, imaging, bioinformatics and systems biology. Research: The central hypothesis of this proposal is that ST2+ and CXCR3+ Tregs in the lung of influenza- infected mice are distinct Treg subsets with unique requirements for activation and non-redundant functions. Specifically, we propose that ST2+ Tregs are ?innate Tregs? that modulate IL-17 producing innate-like gd T cells, while CXCR3+ Tregs are ?adaptive Tregs? that directly influence the antigen specific effector responses. Furthermore, we present data that the chemokine receptor CCR5 is required for the formation of ST2+ Tregs in the lung during influenza while IFN? signaling specifically reduces the number of these cells. This suggests that modulation of these pathways could specifically augment ST2+ Treg function and fine-tune innate inflammation without compromising the adaptive response and viral control. We therefore plan to use mouse models, conditional knockout mice, transcriptome analysis and imaging to understand the role and regulation of the these Treg subsets in influenza. Specifically, we propose (1) To determine the roles of the ST2+ and CXCR3+ Treg subsets during influenza infection, (2) To determine the role of CCR5 in ST2+ Treg generation, (3) To understand the significance of IFN? mediated downregulation of the ST2+ Treg subset during influenza.